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Biomedical subjects

P Buchan

Publications and source records attributed to P Buchan.

17 recordsLinked to original sources
PubMed2007

Smarter candidate selection--utilizing microdosing in exploratory clinical studies.

Microdosing offers a faster and potentially less expensive approach to obtaining human in vivo PK data in early clinical drug development. It encompasses the use of pharmacologically inactive doses of test drug in the low microgram range along with ultrasensitive assay methods (PET, AMS) to assess human exposure in order to extrapolate the PK of higher, clinically more relevant doses, assuming linear PK. This strategy allows early evaluation of systemic clearance, oral bioavailability as well as sources of intersubject variability and questions of specific metabolite formation. It does take advantage of reduced regulatory requirements of preclinical safety studies, bulk drug synthesis (CMC requirements) and easier formulation options, e.g., as part of an exploratory IND; however, this is counterbalanced by a need to synthesize radiolabeled test compound and the development of a sophisticated analytical method. Ongoing studies will determine the predictability of human PK using Microdosing methods.

Animals↗
PubMed2002

Clinical pharmacokinetics of frovatriptan.

OBJECTIVE: To review available data on the clinical pharmacokinetics of frovatriptan. BACKGROUND: Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from that of the currently available triptans. METHODS: Studies of healthy volunteers, subjects with renal or hepatic impairment, elderly subjects, and patients with migraine during and between attacks were reviewed. RESULTS: Oral bioavailability of frovatriptan is 22% to 30%, and although the time to maximum concentration is typically 2 to 3 hours, approximately 60% to 70% of plasma maximum concentration is achieved within 1 hour of dosing. Frovatriptan distributes into erythrocytes, with binding reversible and time dependent. The relatively long terminal elimination half-life (about 26 hours) confers good systemic exposure and may produce a long duration of therapeutic action, thus reducing migraine recurrence and the need for redosing. Systemic exposure to frovatriptan generally correlates with dose between 1 and 100 mg. Blood and plasma frovatriptan concentrations are consistently higher in females, but there is no need to adjust dose according to gender. Pharmacokinetics are essentially unaffected by food and were predictable after repeat dosing; steady state is approached in about 4 to 5 days. Pharmacokinetics were changed only slightly in subjects with renal impairment or mild-to-moderate hepatic impairment, elderly individuals, and during migraine attacks. Frovatriptan is principally metabolized by the CYP1A2 isoenzyme of cytochrome P-450 and is cleared by the kidney and liver, each having sufficient capacity to compensate for impairment of the other. CONCLUSIONS: Frovatriptan can be taken without regard for food intake, and because of the large therapeutic margin and shallow dose-response curve, there is no need for dosage adjustment in the elderly, in women taking a combined oral contraceptive, in patients with mild-to-severe renal impairment, mild-to-moderate hepatic impairment, or according to gender. The long duration of exposure may reduce the likelihood of early migraine recurrence.

Administration, Oral↗
PubMed2002

Frovatriptan: a review of drug-drug interactions.

OBJECTIVE: To investigate the potential for interactions involving drugs likely to be coadministered with frovatriptan. BACKGROUND: Frovatriptan is a new 5-hydroxytryptamine (5-HT)(1B/1D) agonist. Preclinical data suggest that the pharmacokinetic and pharmacological profile of frovatriptan may differ from that of the currently available triptans. METHODS: The potential for interactions between frovatriptan and other drugs was investigated using in vitro methods, studies in healthy volunteers, and retrospective analysis of data from phase I trials. RESULTS: In vitro, frovatriptan was principally metabolized by cytochrome P-450 (CYP) 1A2 but was found not to be an inhibitor or inducer of this or other CYP isoenzymes. Frovatriptan was only a weak inhibitor of monoamine oxidase at very high concentrations in vitro and was not a substrate for this enzyme (unlike some other triptans). Coadministration with moclobemide, at doses known to inhibit monoamine oxidase-A, did not affect the pharmacokinetics of frovatriptan. Binding to plasma proteins was low (15%), and binding to erythrocytes was moderate (60%) and unlikely to be a source of interaction with other drugs. The pharmacokinetics of frovatriptan were not affected by moderate alcohol intake. There were slight increases in area under the curve and maximum concentration on concomitant administration with the combined oral contraceptives, propranolol, and fluvoxamine; and slight decreases in these parameters on concomitant administration with ergotamine and in tobacco smokers; these findings were considered to have no clinical significance in view of frovatriptan's large therapeutic index (well tolerated at doses ranging from 2.5 to 40 mg). These effects can be attributed primarily to modification of CYP1A2 activity but their impact is limited, probably due to frovatriptan also undergoing renal clearance and the likely role of blood cell binding in controlling the amount of unbound drug available for elimination. CONCLUSIONS: Because it has no inhibitory or inducing effect on CYP isoenzymes and is only slightly bound to plasma proteins, it is unlikely that frovatriptan will alter the pharmacokinetics of concomitantly administered drugs. Frovatriptan, therefore, appears to have a low risk of interaction with other drugs, and adjustments of dose are unlikely to be required when it is coadministered with other agents.

Acute Disease↗
PubMed1998

Growth-inhibitory effects of the synthetic retinoid CD437 against ovarian carcinoma models in vitro and in vivo.

The activity of CD437¿6-[3-(1-adamantyl)-4 hydroxyphenyl]-2-naphthalene carboxylic acid¿, a relatively selective activator of RAR-gamma, was evaluated against four human ovarian-carcinoma cell lines : PE01, PE04 (a Pt-resistant in vivo-derived counterpart of PE01), PE01CDDP (a Pt-resistant in vitro-derived model of PE01) and PE014. Growth inhibition was observed after 3 and 6 days of exposure to sub-micromolar concentrations as assessed by a reduction in cell number. IC50 values against PE01, PE04, PE01CDDP and PE014 were 0.09, 0.21, 0.12 and 0.28 microM (day 3) and 0.1, 0.14, 0.07 and 0.17 microM (day 6), respectively. Cisplatin-resistant cell lines were as responsive as cisplatin-sensitive lines, indicating potential activity in resistant disease. CD437 was also evaluated against the PE04 xenograft grown in nude mice using daily doses of 20 (days 0-4) and 10 mg/kg (days 0-4 and 7-11) given either by i.p. delivery or oral administration. Significant growth inhibition (P < 0.05) was obtained for both doses and by both routes. These data provide further support for the view that retinoids have value for the treatment of ovarian cancer.

Administration, Oral↗
PubMed1994

Repeated topical administration of all-trans-retinoic acid and plasma levels of retinoic acids in humans.

BACKGROUND: Vitamin A ingestion raises plasma levels of several potentially teratogenic retinoic acids (RAs) with all-trans and 13-cis configuration, but definitive data concerning the consequences of topical administration of all-trans-RA are lacking. OBJECTIVE: The study objective was to investigate the potential for inducing systemic activity after topical administration of 0.025% all-trans-RA by measuring plasma retinoid levels. METHODS: Plasma levels of all-trans-RA, 13-cis-RA, and 4-oxo-13-cis-RA were measured in four healthy subjects before, during, and after 14 daily topical applications of all-trans-RA. RESULTS: Topical administration of all-trans-RA did not significantly increase plasma levels of all-trans-RA, 13-cis-RA, and 4-oxo-13-cis-RA. Significant decreases in levels of these RAs observed during the night may reflect diurnal variations of retinoid metabolism or lowered absorption of dietary vitamin A. CONCLUSION: Diurnal and nutritional factors influence plasma levels of endogenous retinoids to a greater extent than topical administration of all-trans-RA at doses used for acne therapy, which on the basis of these results appears unlikely to induce systemic effects.

Administration, Topical↗
PubMed1993

Evaluation of the teratogenic risk of cutaneously administered retinoids.

In current cutaneous retinoid therapy systemic exposure is low and the risk of teratogenesis appears to be limited. However, new indications, altered posologies and the introduction of new synthetic retinoids demand continuous assessment of the teratogenic risk. Teratogenicity testing of new substances in animals is only of value if accompanied by detailed pharmacokinetic analysis to establish the relationships between the levels of parent compound and metabolite in both maternal plasma and fetal tissues and teratogenic events. This information should be compared to the maximum of relevant pharmacokinetic data which can be ethically obtained in man or from human tissues. The presence or absence of teratogenic effects following cutaneous administration of retinoids in animals has, as such, little direct bearing on the risk in man. Two special cases exist where teratogenic risk can be evaluated directly in man without reference to animal studies. The first concerns substances whose teratogenic potential has been established in man by other routes of administration permitting a comparison with the cutaneous route on a pharmacokinetic basis. The second concerns the cutaneous administration of endogenously occurring substances and their eventual disturbance of systemic retinoid equilibrium.

Administration, Topical↗
PubMed1992

Capsaicin-induced bronchoconstriction in the guinea-pig: contribution of vagal cholinergic reflexes, local axon reflexes and their modulation by BW443C81.

1 The objective of the study was to investigate the central vagal and local axon reflex components of bronchoconstrictor responses evoked by inhalation of capsaicin aerosol in anaesthetized guinea-pigs. This was accomplished by comparing the effects of bilateral vagotomy, atropine and the peripherally-acting polar enkephalin analogue, BW443C81, on bronchoconstrictor responses evoked by capsaicin. The effects of codeine were also determined. 2 Aerosols of capsaicin were generated from a 0.9 microgram ml-1 solution. Inhalation of capsaicin aerosol in 5, 10 and 15 breaths evoked dose-related bronchoconstrictor responses. The responses were immediate in onset and of extended duration. 3 Capsaicin-induced bronchoconstrictor responses were significantly inhibited following bilateral vagotomy or atropine (0.3 mg kg-1, i.v.) pretreatment by 46% +/- 14% (P less than 0.05) and 59% +/- 13% (P less than 0.01), respectively. 4 Administration of BW443C81 by intravenous infusion (3, 30 and 100 micrograms kg-1 min-1) caused a significant inhibition of capsaicin-induced bronchoconstrictor responses which achieved a greater maximum than either bilateral vagotomy or atropine. Codeine (100 micrograms kg-1 min-1, i.v.) did not significantly inhibit the bronchoconstrictor responses. 5 Inhibition of capsaicin-induced bronchoconstrictor responses by BW443C81 (30 micrograms kg-1 min-1, i.v.) was significantly (P less than 0.05) reduced by the peripherally-acting opioid antagonist N-methyl nalorphine (100 micrograms kg-1 min-1, i.v.). 6 These results show that capsaicin-induced bronchoconstrictor responses are mediated by at least two mechanisms, a vagal and/or cholinergic reflex pathway and a non-cholinergic pathway. BW443C81, but not codeine, significantly inhibited (P < 0.005) both mechanisms of capsaicin-induced bronchoconstriction probably by an action on peripheral opioid receptors located on vagal sensory nerves.

Amino Acid Sequence↗
PubMed1986

Corticotropin-releasing factor inhibits neurogenic plasma extravasation in the rat paw.

Increased exudation of plasma proteins, as measured by Evans blue leakage into the innervated paw, was produced by antidromic stimulation of the saphenous nerve in the pentobarbital-anesthetized rat. This condition, termed neurogenic plasma extravasation (NPE), was inhibited by morphine, FK 33,824 (a stabilized enkephalin analog), dynorphin (1-13), dynorphin(1-10)amide and corticotropin-releasing factor (CRF) at median effective doses of 2700, 0.45, 1180, 4050 and 5.6 nmol/kg i.v., respectively. The inhibitory effect of CRF was present when injected up to 60 min before electrical stimulation of the nerve. By contrast, the effects of morphine and FK 33,824 were shorter in duration, lasting for only 20 to 30 min before nerve stimulation. Inhibition of NPE by morphine, FK 33,824 dynorphin (1-13) and dynorphin (1-10)amide was blocked by naloxone, 1 mg/kg i.v., but the CRF inhibition was not affected. CRF inhibited NPE in both hypophysectomized and adrenalectomized rats, indicating that its effects were not due to secondary release of endogenous opioid peptides. The inhibitory effect of CRF on NPE was also separable from its hypotensive properties and could be obtained at intradermal doses of CRF into the paw skin which were approximately 11 times lower than the i.v. doses. Intracerebroventricular injection of CRF did not affect the tail-flick latency of rats to warm water. CRF administered i.v. in mice did, however, inhibit writhing responses to phenylbenzoquinone (PBQ), suggesting possible peripheral antinociceptive properties.

Adrenalectomy↗
PubMed1984

Peripheral opioid receptors located on the rat saphenous nerve.

Morphine and ethylketocyclazocine inhibited neurogenic plasma extravasation (NPE) elicited by antidromic stimulation of the saphenous nerve of the rat. The inhibitory effects of the opiate agonists were antagonised by naloxone and N-methyl nalorphine and independent of any local anaesthetic actions since inhibition of NPE was observed on superfusion of the saphenous nerve with lignocaine, but not with morphine or ethylketocyclozocine. The opiate agonists also failed to inhibit extravasation induced by intradermal administration of substance P. The findings support the contention that specific opioid receptors are located on the peripheral part of primary afferent neurones and these receptors may contribute significantly to peripherally mediated antinociceptive effects of opioids.

Animals↗
PubMed1984

Shoulder-out immersion in pregnant women.

In the laboratory, water immersion or lower body positive pressure produces significant diuresis and natriuresis. Shoulder-out immersion appeared to induce significant diuresis and natriuresis in 42 pregnant women who were exercising in swimming pools. Lower body positive pressure (pressure calf sleeves) or Hubbard tanks (bathtubs) was not associated with increased renal function. In selected pregnant women with abnormal water distribution, shoulder-out immersion may prove to be effective therapy.

Blood Pressure↗
PubMed1978

The plasma half-life of placental hormones.

Blood was collected from 12 women following Caesarean section or normal delivery at term. The decline in plasma concentration of total oestriol, oestriol sulphate, oestriol glucosiduronate, unconjugated oestriol, human placental lactogen and pregnancy specific beta1 glycoprotein following delivery of the placenta was studied for 120 hours. The steroids and human placental lactogen fell very rapidly but pregnancy specific beta1 glycoprotein declined much more slowly. Analysis of the curves of puerperal decline suggests that the oestriol moieties are distributed in many compartments of the mother but that the proteins penetrate only to the plasma and the interstitial fluid.

Estriol↗
PubMedDate not supplied

Peripheral antinociceptive effects of N-methyl morphine.

Morphine and N-methyl morphine were compared in two antinociceptive tests in mice, the hotplate and acetic acid-induced writhing. Whereas morphine was active in both models, N-methyl morphine was only active in the writhing model. In this model, the antinociceptive effects of N-methyl morphine were antagonized by both naloxone and N-methyl nalorphine. In separate experiments the two quaternary analogues were both [14C]-labelled and shown not to penetrate the blood brain barrier. These results indicate a peripheral site of action for the opioid antinociceptive effects of N-methyl morphine in the writhing model.

Analgesia↗